1. Field of the Invention
The present invention relates to a process for producing 5-fluorouracil derivative having the formula ##STR2## wherein R represents hydrogen atom and 2-tetrahydrofuryl group.
2. Description of the Prior Art
The 5-fluorouracil derivatives having the formula I, are useful as medicines and intermediates for medicines. Especially, the N.sub.1 (2-tetrahydrofuryl)-5-fluorouracil (R .dbd. H in formula I) has been known to be oral antineoplastic agent having low toxicity.
Heretofore, the following processes have been known to produce N-substituted-fluorouracils.
(1) The process for reacting mercury salt of 5-fluorouracil with 2-chlorotetrahydrofuran. (British Pat. No. 1,168,391 and Hiller et al.; Dokl Akad. Nauk. (USSR) 176[2]332, 1967).
(2) The process for reacting 2,4-bis(trimethylsilyl)-5-fluorouracil with 2-chlorotetrahydrofuran (British Pat. No. 1,168,391).
(3) The process for reacting 2,4-bis(trimethylsilyl)-5-fluorouracil with 2-acyloxytetrahydrofuran or 2-alkoxytetrahydrofuran. (Japanese Unexamined Patent Publication Nos. 50384/1975 and 105674/1975).
(4) The process for reacting 5-fluorouracil with an alkali metal hydride and then reacting the resulting alkali metal salt of 5-fluorouracil with 2-halogenotetrahydrofuran. (Japanese Unexamined Patent Publication No. 8282/1976).
However, in these conventional processes, the starting materials such as 2-chlorotetrahydrofuran which are easily decomposed and are produced by using stimulus gas are used and the yields are low.
In the other processes, 2-acyloxytetrahydrofuran or 2-alkoxytetrahydrofuran of which manufacture causes dangerous exothermic reaction is needed or the expensive raw material such as hexamethyldisilasane is needed.
Accordingly, from the viewpoint of cost or safety of the operation, these conventional processes are not satisfactory.
In Dokl, Akad, Nauk, (USSR), it is described that a condensed product could not be obtained by direct reaction of the substituted uracil with 2,3-dihydrofuran. In C.W. Noell et al.; J. Heterocyclic Chem. 3, 5, (1966), the similar fact is described.
Accordingly, it has been considered to be impossible to directly react 5-fluorouracil with 2,3-dihydrofuran.
However, the inventors have studied the reactivity of 5-halogeno-substituted uracils in detail, and have found that the reaction of 5-halogeno-substituted uracil with 2,3-dihydrofuran is surprisingly resulted in a polar aprotic solvent at higher than specific temperature under pressure. Moreover, the inventors have found that the reaction can be promoted with a catalyst.